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Abstract:

This invention relates to therapeutic compositions, particularly
sprayable aqueous compositions, and unit dose formulations comprise
ketorolac or a pharmaceutically acceptable salt, alone or in combination
with lidocaine or a pharmaceutically acceptable salt thereof. The
compositions are nasally administered to a subject in need thereof to
treat pain or inflammation.

Claims:

1. An aqueous solution suitable for nasal administration to a subject,
which solution comprises (a) about 25% w/v to about 38% w/v of ketorolac,
(b) water, and (c) a pharmaceutically acceptable pH adjuster to maintain
the solution at a pH of about 4.5 to 8.

2. The solution of claim 1, wherein ketorolac is present as a racemic
mixture.

3.-4. (canceled)

5. The solution of claim 1, comprising about 30% w/v of ketorolac
tromethamine.

6.-15. (canceled)

16. The solution of claim 1, contained in a vessel suitable for spraying
the solution into a subject's nostril.

17. The solution of claim 16, wherein the vessel is in a size suitable to
contain about 0.1 to 4 mL of the solution.

18. (canceled)

19. The solution of claim 16, in combination with a label instruction
providing for administration of 50 to about 100 microliters of the
solution per nostril.

20.-21. (canceled)

22. A solution suitable for nasal administration to a subject comprising:
(a) about 30% w/v of racemic ketorolac tromethamine, (b) about 0.02% w/v
of disodium edetate, (c) about 0.68% w/v of potassium phosphate
monobasic, (d) sodium hydroxide to adjust the pH to 7.2, and (e) water to
100% w/v.

23.-24. (canceled)

25. A method for treating pain or inflammation in a subject in need of
such treatment, comprising intranasally administering to a subject the
solution of claim 1.

26. A method for treating pain or inflammation in a subject in need of
such treatment, comprising intranasally administering to a subject the
solution of claim 22.

27.-31. (canceled)

32. A unit dose formulation for nasal administration to one or two
nostrils of a subject, comprising (a) about 12 to about 38 mg of
ketorolac per nostril, and (b) water, wherein said unit dose has a volume
of 100 microliters or less per nostril and wherein the concentration of
ketorolac is greater than 22.5% w/v.

33. The unit dose formulation of claim 32, wherein the volume is about 50
to about 100 microliters per nostril.

34. The unit dose formulation of claim 32, wherein the volume is about
100 microliters per nostril.

35. (canceled)

36. The unit dose formulation of claim 33 for administration to two
nostrils, comprising about 30 mg of ketorolac tromethamine per nostril,
wherein the unit dose has a volume of about 100 microliters per nostril.

37. The unit dose formulation of claim 32, wherein the volume is about 50
microliters per nostril.

38. (canceled)

39. The unit dose formulation of claim 37 for administration to two
nostrils, comprising about 15 mg of ketorolac tromethamine per nostril,
wherein the unit dose has a volume of about 50 microliters per nostril.

40.-44. (canceled)

45. The unit dose formulation of claim 32, wherein the unit dose
formulation is contained in a vessel equipped with a device for spraying
the unit dose formulation into the nostril of the subject.

46. The unit dose formulation of claim 45, wherein the vessel further
comprises a metering chamber and wherein the metering chamber holds about
50 to about 100 microliters.

47. The unit dose formulation of claim 32, in combination with a label
instruction providing for administration of about 15 to about 30 mg of
ketorolac per nostril.

48.-51. (canceled)

52. A method for treating pain or inflammation in a subject in need of
such treatment, comprising intranasally administering a unit dose
formulation of claim 32.

53.-61. (canceled)

Description:

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. §119(e) of
U.S. Provisional Patent Application Ser. Nos. 61/061,522, filed on Jun.
13, 2008, and 61/160,254, filed on Mar. 13, 2009, both of which are
incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to a pharmaceutical composition and a unit
dose formulation of the pharmaceutical composition suitable for
intranasal administration, which includes ketorolac or its
pharmaceutically acceptable salts as the active analgesic and
anti-inflammatory ingredient, and optionally lidocaine to reduce the
sensation of stinging and to improve efficacy. This invention also
relates to a therapeutic method that provides for the nasal
administration of the composition to a subject to treat pain or
inflammation.

BACKGROUND OF THE INVENTION

[0003] Ketorolac or 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
has the following Formula (I):

##STR00001##

It has been known for several years (U.S. Pat. No. 4,089,969) and is used
in human therapy as an analgesic and an anti-inflammatory as the
tromethamine salt. U.S. Pat. No. 4,089,969 is incorporated herein by
reference in its entirety.

[0004] Both the racemic form and each of the dextro and levo isomers of
this compound are known. Many pharmaceutically acceptable salts, the most
commonly used of which is the tromethamine
(2-amino-2-hydroxymethyl-1,3-propanediol) salt, are also known.

[0005] Ample literature is available on ketorolac (for instance,
"Ketorolac--A review of its pharmacodynamic and pharmacokinetic
properties and its therapeutic potential", Drugs 39(1): 86-109, 1990). It
is described as a drug with considerably higher analgesic activity than
many other non-steroidal anti-inflammatory drugs. Most significantly, it
has analgesic activity comparable to that of the opiates, such as
morphine, without the well-known side effects of the latter.

[0006] It is known that ketorolac can be formulated as a nasally
administrable composition. See U.S. Pat. No. 6,333,044 to Recordati,
which is incorporated herein by reference in its entirety. U.S. Patent
Application Publication No. 2009/0042968, the content of which is
incorporated hereby by reference in its entirety, describes a composition
that is a combination of ketorolac and a local anesthetic for nasal
administration to reduce the stinging sensation. Specifically, the
composition disclosed in U.S. Patent Application Publication No.
2009/0042968 comprises an effective amount of ketorolac in combination
with a pharmaceutically acceptable diluent and 4%-10% weight to volume
(w/v) of a local anesthetic, e.g., lidocaine hydrochloride (preferably
5-6% w/v). Preferably the composition is a sprayable aqueous solution
comprising ketorolac tromethamine present at a level of about 2.5-22.5%
w/v, and lidocaine hydrochloride present at a level of 4% to 10% w/v.

SUMMARY OF THE INVENTION

[0007] One aspect of this invention is a unit dose formulation for nasal
administration to one or two nostrils comprising:

[0008] (a) greater than 12 to about 38 mg of ketorolac per nostril at a
concentration of greater than 22.5% w/v; and

[0009] (b) a pharmaceutically acceptable carrier;

[0010] wherein said unit dose has a volume of 100 microliters or less per
nostril.

[0011] In another aspect, the 100 microliters of composition further
comprises up to about 10 mg of lidocaine at a concentration of from 4% to
10% w/v. In some embodiments, the unit dose comprises up to about 38 mg
and preferably about 30 mg of ketorolac tromethamine and about 6 mg of
lidocaine hydrochloride per nostril, and the volume is about 100
microliters per nostril. In some embodiments, the unit dose comprises up
to about 17 mg and preferably about 15 mg of ketorolac tromethamine and
about 3 mg of lidocaine hydrochloride per nostril, and the volume is
about 50 microliters per nostril.

[0012] Another aspect of this invention is a composition for spraying into
a human subject's nasal passage that comprises:

[0013] (a) a pharmaceutically acceptable carrier;

[0014] (b) greater than 22.5 to about 38% w/v of ketorolac, or a
pharmaceutically acceptable salt (e.g., tromethamine); and

[0015] (c) optionally other pharmaceutically acceptable excipients.

[0016] Another aspect of this invention is a composition for spraying into
a human subject's nasal passage that comprises:

[0017] (a) a pharmaceutically acceptable carrier;

[0018] (b) greater than 22.5 to about 38% w/v of ketorolac, or a
pharmaceutically acceptable salt (e.g., tromethamine);

[0019] (c) about 4 to 10% w/v of lidocaine, or a pharmaceutically
acceptable salt (e.g., hydrochloride); and

[0020] (d) optionally other pharmaceutically acceptable excipients.

[0021] Another aspect of this invention is a method for treating pain or
inflammation in a subject in need of such treatment, which comprises
intranasally administering the composition of this invention to the
subject.

[0022] Another aspect of this invention is a method for treating pain or
inflammation in a subject in need of such treatment, which method
comprises administering a unit dose formulation of this invention to one
nostril of the patient. In some embodiments, the method comprises
administering a unit dose formulation of this invention to each nostril
of the patient.

[0023] Another aspect of the invention is the composition of the invention
in a vessel equipped with a device for spraying the composition into a
patient's nasal passage.

[0024] Another aspect of the invention is the unit dose formulation of the
invention in a single-use vessel equipped with a device for spraying the
composition into a patient's nasal passage. Another aspect of the
invention is the unit dose fog ululation of the invention in vessel
equipped with a device for spraying the composition into a patient's
nasal passage wherein the vessel comprises a head space with an oxygen
content that is less than the normal atmospheric oxygen content.

[0025] Another aspect of the invention is the use of greater than about
22.5 to 38% w/v of ketorolac or a pharmaceutically-acceptable salt
thereof, optionally in combination with about 4% to about 10% w/v of
lidocaine or a pharmaceutically acceptable salt thereof, to prepare a
composition for nasal administration to a subject for the treatment of
pain or inflammation.

[0026] In some embodiments, the pain is the result of a trauma inflicted
on the subject. In some embodiments, the pain is the result of a medical
operation performed on the subject. In some embodiments, the pain is
pathological. In some embodiments, the pain is neuropathic. In some
embodiments, the pain is migraine or other headache pain.

[0027] These and other embodiments are described in details below.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0028] Before the compositions and methods are described, it is to be
understood that the invention is not limited to the particular
methodologies, protocols, and reagents described, as these may vary. It
is also to be understood that the terminology used herein is intended to
describe particular embodiments of the present invention, and is in no
way intended to limit the scope of the present invention as set forth in
the appended claims.

[0029] Unless defined otherwise, all technical and scientific terms used
herein have the same meanings as commonly understood by one of ordinary
skill in the art to which this invention belongs. Although any methods
and materials similar or equivalent to those described herein can be used
in the practice or testing of the present invention, the preferred
methods, devices, and materials are now described. All technical and
patent publications cited herein are incorporated herein by reference in
their entirety. Nothing herein is to be construed as an admission that
the invention is not entitled to antedate such disclosure by virtue of
prior invention.

[0030] In accordance with the present invention and as used herein, the
following terms are defined with the following meanings, unless
explicitly stated otherwise.

[0031] As used in the specification and claims, the singular form "a",
"an" and "the" include plural references unless the context clearly
dictates otherwise. For example, the term "a pharmaceutically acceptable
salt" includes a plurality of pharmaceutically acceptable salts,
including mixtures thereof.

[0032] As used herein, the term "comprising" or "comprises" is intended to
mean that the compositions and methods include the recited elements, but
not excluding others. "Consisting essentially of" when used to define
compositions and methods, shall mean excluding other elements of any
essential significance to the combination for the stated purpose. Thus, a
composition consisting essentially of the elements as defined herein
would not exclude other materials or steps that do not materially affect
the basic and novel characteristic(s) of the claimed invention.
"Consisting of" shall mean excluding more than trace amount of elements
of other ingredients and substantial method steps. Embodiments defined by
each of these transition terms are within the scope of this invention.

[0033] The term "about" when used before a numerical designation, e.g.,
pH, temperature, amount, concentration, and molecular weight, including
range, indicates approximations which may be varied by (+) or (-) 5%, 1%
or 0.1%.

[0034] The term "greater than" when used in front of a number refers to a
range that does not include the number. For example, "greater than 22.5%"
does not include 22.5%.

[0035] "Ketorolac" refers to the chemical compound of
5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid which has the
following formula (I):

##STR00002##

The name ketorolac encompasses individually or collectively the racemic
mixture, a scalemic (or enantiomerically enriched) mixture, optically
active compound, or a pharmaceutically acceptable salt of any of the
above. Many pharmaceutically acceptable salts of ketorolac, for example
ketorolac tromethamine, are known. As used herein, a racemic mixture of
ketorolac is a mixture having equal amount of the two enantiomers of
Formula (I). A scalemic or enantiomerically enriched mixture of ketorolac
is a mixture where the amount of one of the enantiomers of Formula (I) is
larger than the other enantiomer. An optically active compound may
include enantiomerically enriched or enantiomerically pure compound.
Enantiomerically pure compound refers to ketorolac having more than 99%,
preferably 99.5%, or 99.9% of one of the enantiomers relative to the
total amount of ketorolac.

[0036] "Lidocaine" refers to the chemical compound of
2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide, which has the formula
(II):

##STR00003##

or a pharmaceutically acceptable salt thereof. Many pharmaceutically
acceptable salts of lidocaine are known. Non-limiting examples of such
salts are lidocaine hydrochloride and lidocaine methanesulphonate. As
used herein, the term "lidocaine" refers to the compound or any of its
pharmaceutically acceptable salts, unless otherwise indicated.

[0037] The term "subject," "individual" or "patient" refers to a human.

[0038] The term "aggregate daily dose" refers to the total amount of drug
or compound administered to a patient in a 24 hour period. The aggregate
daily dose should not exceed the maximum dosing allowed by the relevant
regulatory agency, such as the United States Food and Drug Administration
(FDA) or the European Medicines Agency (EMEA).

[0039] The term "pharmaceutically acceptable salt" refers to
pharmaceutically acceptable salts derived from a variety of organic and
inorganic counter ions well known in the art and include, by way of
example only, sodium, potassium, calcium, magnesium, ammonium,
tromethamine, and tetraalkylammonium, and when the molecule contains a
basic functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate (also known as
methanesulfonate), acetate, maleate, and oxalate. Suitable salts include
those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook
of Pharmaceutical Salts Properties, Selection, and Use; 2002.

Unit Dose

[0040] Administering ketorolac tromethamine nasally has certain advantages
over administering the compound by injection or orally. These advantages
are discussed in prior art references U.S. Pat. No. 6,333,044 ("the '044
patent") and U.S. Patent Application Publication 2009/0042968 ("the '968
Publication"). The latter reference teaches that ketorolac tromethamine
is successfully combined with a local anesthetic, e.g. lidocaine
hydrochloride, to reduce the stinging effect that some patients
experience with the nasal administration of ketorolac tromethamine alone.
Because the '044 patent and the '968 Publication teach the maximum
concentration of ketorolac tromethamine for nasal administration to be
22.5% w/v, it was thought that higher concentrations of the compound
could not be achieved. Indeed, with 4 to 6% lidocaine in the solution, it
was expected that increasing the concentration of ketorolac tromethamine
would increase the likelihood of precipitation and instability of the
solution perhaps reducing the shelf life of the product.

[0041] Realizing that in some instances, it may be advantageous to deliver
more of the active, optionally along with the lidocaine hydrochloride, in
a unit dose to a patient, it was attempted to deliver more drug by
increasing the volume of the solution per nostril to the patent. Although
up to 200 microliters can be administered to one nostril, this large
volume can lead to significant drainage of the solution from the nostril
and to loss of the active ingredient, due to the limited capacity of the
nostril and surface area of nasal mucosa. Thus, it was found that the
amount of drug administered to a nostril may not be effectively increased
simply by increasing the volume administered. It was further found that
the maximum volume that can be absorbed by a nostril is about 125
microliters. Excess amount can run out of the nostril, resulting in
undesirable reduced therapeutic effect and/or side effects to areas
contacted by the running liquid. This can lead to reduced patient
compliance. Preferably, the volume of the unit dose does not exceed about
100 microliters; with 75, 50, or 25 microliters per patient nostril
providing the highest likelihood of good patient acceptance and
compliance.

[0042] Surprisingly, we have now found that it is possible to prepare
analgesic/anti-inflammatory intranasal formulations containing a high
concentration of the active ingredient ketorolac for the treatment of
pain and/or inflammation in a human subject. It is contemplated that the
formulations containing high concentration of ketorolac are suitable for
intranasal administration to obtain a stronger therapeutic effect than
that obtained by the previously described intranasal formulations of
ketorolac and yet limit the volume administered to at or below the
capacity of the nostril to avoid drainage, increase the likelihood of
patient acceptance and thus compliance, increase bioavailability and/or
provide more reproducible pharmacokinetic profile. The high concentration
also allows a high unit dosage of ketorolac to be administered to a
patient in need thereof with a single spray to one or each nostril.
Further, it is contemplated that the concentration of lidocaine, or a
salt thereof, would not need to be increased with an increase in the
concentration of ketorolac and can still effectively reduce the stinging
sensation caused by the increased concentration of ketorolac.

[0043] This discovery leads to various aspects of this invention, which
will be discussed hereinafter. These aspects include a novel composition
particularly suited for use in a unit dosage, a novel device using the
composition for nasal delivery, a method for treating pain or
inflammation using the composition, and a system for delivering the
composition that comprises the composition in the device with
instructions for use.

[0044] In one of its aspect, the composition of this invention comprises a
solution of ketorolac tromethamine that contains more than 22.5% w/v
ketorolac tromethamine at a pH suitable for nasal delivery to a human
subject, optionally in combination with about 4-10% w/v of lidocaine as a
pharmaceutically acceptable salt.

[0045] Thus, in one embodiment, this invention relates to a unit dose
formulation for nasal administration to one or two nostrils comprising

[0046] (a) greater than 12 to about 38 mg of ketorolac per nostril at a
concentration of greater than 22.5% w/v; and

[0047] (b) water;

[0048] wherein said unit dose has a volume of 100 microliters or less per
nostril.

[0049] In another embodiment, this invention relates to a unit dose
formulation for nasal administration comprising

[0050] (a) greater than 12 to about 17 mg of ketorolac per nostril at a
concentration of greater than 22.5% w/v; and

[0051] (b) water;

[0052] wherein said unit dose has a volume of about 50 microliters or less
per nostril.

[0055] In some embodiments, the unit dose further comprises about 2 to
about 10 mg of lidocaine or a pharmaceutically acceptable salt thereof,
e.g. lidocaine hydrochloride, provided that the amount of lidocaine does
not exceed about 10% w/v and is more than about 4 w/v. In some
embodiments, the unit dose formulation further comprises about 2, 3, 4,
5, 6, 7, 8, 9, or 10 mg of lidocaine hydrochloride.

[0056] In some embodiments, a subject is administered about 50 to 100
microliters per nostril to one or both nostrils. For example, for an
acute episode of migraine attack, two single sprays of about 100
microliters, each containing about 30 mg of ketorolac can be administered
to each nostril to provide for a unit dose of about 60 mg of ketorolac,
which is expected to provide fast relief of the pain, and/or to stop the
pain from aggravating and to prevent or to eliminate other symptoms
associated with migraine, such as nausea and sensitivity to light and
sound. In some embodiments, a unit dose of about 30 mg can be
administered by two sprays of about 50 microliters containing about 15 mg
of ketorolac, one to each nostril so that all drug can be retained in the
nostril(s). This reduced volume is expected to provide increased
bioavailability and/or better pharmacokinetics yet maintain the
therapeutic effect.

[0057] It is contemplated that such a high dosage of ketorolac would
deliver higher analgesic or anti-inflammatory efficacy yet would not
increase the side effects significantly. It is further contemplated that
notwithstanding the higher dose of ketorolac in the formulations of this
invention, the amount of lidocaine present in the formulation will
inhibit stinging during application while also minimizing or eliminating
numbing in the nasal mucosa and/or the throat.

[0058] In some embodiments, the unit dose is in the form of an aqueous
solution.

[0059] In some embodiments, the unit dose comprises ketorolac
tromethamine. In some embodiments, the unit dose comprises about 30 mg of
ketorolac tromethamine and has a volume of about 100 microliters per
nostril. In some embodiments, the unit dose comprises about 15 mg of
ketorolac tromethamine and has a volume of about 50 microliters per
nostril. In some embodiments, the unit dose is for administration to two
nostrils which unit dose comprises about 15 mg of ketorolac tromethamine
and has a volume of about 50 microliters per nostril. In some
embodiments, the unit dose is for administration to one nostril, which
unit dose comprises about 15 mg of ketorolac tromethamine and has a
volume of about 50 microliters. In some embodiments, the unit dose is for
administration to two nostrils which unit dose comprises about 30 mg of
ketorolac tromethamine and has a volume of about 100 microliters per
nostril. In some embodiments, the unit dose is for administration to one
nostril which unit dose comprises about 30 mg of ketorolac tromethamine
and has a volume of about 100 microliters.

[0060] In some embodiments, the unit dose further comprises lidocaine
hydrochloride. In some embodiments, the unit dose comprises about 6 mg of
lidocaine hydrochloride per nostril. In some embodiments, the unit dose
comprises about 3 mg of lidocaine hydrochloride per nostril.

[0061] The unit dose for any particular patient will depend upon a variety
of factors known in the art, including the type and severity of the pain
or inflammation to be treated, the age, body weight, general health, sex
and diet, renal and hepatic function of the patient, and the time of
administration, and will generally be in accordance with the advice of
the attending physician. The unit dose as described above can be
contained in a single container designed to hold a volume of the
pharmaceutical composition such that single or multiple administrations
can be administered from that container.

[0062] In some embodiments, the unit dose formulation further comprises a
chelator, i.e. a substance that binds primarily di- or tri valent
metallic ions (e.g. calcium) that might interfere with the stability or
activity of the active ingredient. Chelators are known to those of skill
in the art by referring to the recent edition of "Remington's
Pharmaceutical Sciences." A preferred chelator is sodium ethylenediamine
tetraacetic acid (sodium EDTA), USP. In some embodiments, the unit dose
comprises about 0.001 to about 1 mg of disodium edetate. In some
embodiments, it comprises about 0.01 to about 0.1 mg of disodium edetate.
In some embodiments, it comprises about 0.02 mg of disodium edetate.

[0063] In some embodiments, the pH of the unit dose is about 4.5 to about
8, or about 4.8 to about 7.5. In some embodiments, the pH of the unit
dose is about 7.2. In some embodiments, the pH is adjusted by a
pharmaceutically acceptable base, such as sodium hydroxide.

[0064] In some embodiments, the pH of the unit dose is further adjusted
and/or maintained by a sufficient amount of a pH buffering agent, such as
potassium phosphate monobasic (KH2PO4), potassium phosphate
dibasic (K2HPO4) or potassium phosphate (K3PO4),
optionally in combination with sodium hydroxide. In some embodiments, the
unit dose comprises about 0.68 mg of potassium phosphate monobasic.

[0065] In some embodiments, the unit dose formulation comprises about 30
mg of ketorolac tromethamine, about 0.02 mg of disodium edetate, about
0.68 mg of potassium phosphate monobasic, sodium hydroxide to adjust pH
to 7.2 and water to about 100 microliters per nostril.

[0066] In some embodiments, the unit dose formulation comprises about 30
mg of ketorolac tromethamine, about 6 mg of lidocaine hydrochloride,
about 0.02 mg of disodium edetate, about 0.68 mg of potassium phosphate
monobasic, sodium hydroxide to adjust pH to 7.2 and water to about 100
microliters per nostril.

[0067] In some embodiments, the unit dose formulation comprises about 15
mg of ketorolac tromethamine, about 0.01 mg of disodium edetate, about
0.34 mg of potassium phosphate monobasic, sodium hydroxide to adjust pH
to 7.2 and water to about 50 microliters per nostril.

[0068] In some embodiments, the unit dose formulation comprises about 15
mg of ketorolac tromethamine, about 3 mg of lidocaine hydrochloride,
about 0.01 mg of disodium edetate, about 0.34 mg of potassium phosphate
monobasic, sodium hydroxide to adjust pH to 7.2 and water to about 50
microliters per nostril.

[0069] In some embodiments, the unit dose formulation is contained in a
vessel equipped with a device for spraying the composition into the nasal
passage of a subject, wherein the composition is an aqueous solution. In
some embodiments, the vessel further comprises a metering chamber. In
some embodiments, the metering chamber is coupled with the spraying
device. An example of a device that can be used for spraying the
composition into a nasal passage of the subject is disclosed in U.S.
application Ser. No. 12/404,250, filed on Mar. 13, 2009, entitled,
"Device for Intranasal Administration," and is incorporated herein by
reference in its entirety. In some embodiments, the vessel comprises a
head space with a reduced oxygen content. In some embodiments, the head
space comprises equal to or less than 10%, 8%, or 5% v/v oxygen.

[0070] In some embodiments, the metering chamber holds about 50
microliters for a single spray. In another embodiment, the metering
chamber holds about 100 microliters for a single spray. In some
embodiments, the volume measured by the metering chamber is adjustable.

[0071] In some embodiments, the unit dose formulation is in combination
with a label instruction providing for administration of about 15 to
about 30 mg of ketorolac per nostril. In some embodiments, the unit dose
formulation is in combination with a label instruction providing for
administration of about 25 to about 60 mg of ketorolac per dose. In some
embodiments, the unit dose formulation is in combination with a label
instruction providing for administration of about 30 or about 60 mg of
ketorolac per dose.

Composition

[0072] In another aspect of this invention, provided are intranasal
formulations suitable for providing the desired high unit dose of
ketorolac to achieve better analgesic/anti-inflammatory therapeutic
effects without exceeding the absorption capacity of nostril. The
formulations of this invention are designed to employ a high
concentration of the active ingredient ketorolac.

[0073] In some embodiments, the intranasal formulations of the invention
comprise concentrations of ketorolac, or a pharmaceutically acceptable
salt, ranging from greater than 22.5 to about 38% w/v, for example about
24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, or
38% w/v, based on the final formulation. In some embodiments, ketorolac
is ketorolac tromethamine. In some embodiments, the composition further
comprises lidocaine, or a pharmaceutically acceptable salt, ranging from
about 4% to 10%, for example about 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/v. In
some embodiments, lidocaine is lidocaine hydrochloride.

[0074] The composition of this invention allows a patient to administer a
large amount of ketorolac with just one spray comprising a maximum of 100
microliters of the composition to one or each of the nostrils. In a
preferred embodiment, the composition of this invention contains 30% w/v
of ketorolac and provides to a patient 60 mg of ketorolac when 100
microliters of solution containing 30 mg of ketorolac is given to each
nostril of the patient. It is contemplated that a higher amount of
ketorolac administered to a patient would produce more effective
analgesic and/or anti-inflammatory relief and/or be useful in treating
more severe pains without significant leakage. This may be beneficial for
treating a migraine pain and/or preventing the deterioration of an acute
migraine attack. In another preferred embodiment, the composition
comprising 30% w/v of ketorolac provides to a patient 30 mg of ketorolac
when 50 microliters of solution containing 15 mg of ketorolac is given to
each nostril of the patient. The smaller volume will further minimize
leakage, provide improved bioavailability and/or pharmacokinetics.

[0075] It has been found that ketorolac produces several degradation
products, such as the 1-keto analog having Formula (III) and the chemical
name of 5-benzoyl-2,3-dihydro-1H-pyrrolizin-1-one, in solution.

##STR00004##

The amount of 1-keto analog produced is generally proportional to the
amount of ketorolac in solution and available oxygen (e.g., in the head
space of the container, such as those described in U.S. patent
application Ser. No. 12/404,250, filed on Mar. 13, 2009, entitled,
"Device for Intranasal Administration,"). It has been found that a higher
concentration of ketorolac can result in a concentration of the 1-keto
analog that is outside an acceptable level, which may cause safety
concerns. It has further been found that the formulations of this
invention may be stored under refrigeration conditions or under air with
reduced oxygen content (e.g., no more than 10% v/v) to allow a high dose
of ketorolac to be administered intranasally to a patient without
compromising the safety requirements.

[0076] In some embodiments, the compositions of this invention comprise a
combination of ketorolac and lidocaine. As described in details in US
Patent Application Publication No. 2009/0042968, the addition of
lidocaine to the 15% w/v ketorolac composition was found to provide
several unexpected advantageous synergistic effects. First, the
combination substantially reduces the stinging sensation caused by
ketorolac. Second, while lidocaine is a local anesthetic that is known to
cause numbness, such numbness is substantially absent or reduced when
lidocaine is combined with ketorolac. Third, combination of 5 to 6% w/v
of lidocaine with ketorolac have been found to decrease the time for
ketorolac to reach its Cmax in a subject's plasma (the "Tmax"), providing
a subject with faster and better pain relief. Surprisingly, when the
concentration of ketorolac is increased to up to 38%, the amount of
lidocaine can be maintained at a level of 4-10% or preferably 5-6% and
yet still inhibits the stinging sensation of ketorolac. Although the
concentration of ketorolac has increased relative to the lidocaine, it is
contemplated that the benefits of decreased Tmax will still be
achieved by the combination of lidocaine with ketorolac.

[0077] Lidocaine and its pharmaceutically acceptable salts, such as
lidocaine hydrochloride, have poor solubility in water under the
physiological pH ranges of 4.5 to 7.2 although it is soluble to greater
than 6% w/v at the lower pH ranges of 2.5 to 4.5. Certain other local
anesthetics, such as benzocaine, also exhibit low solubility at
physiological pH although soluble at low pH. For example, benzocaine
hydrochloride is soluble in water and the solution has a pH of about 1.5.
In the presence of 15% ketorolac, however, precipitation was observed for
both a 6% and a 10% benzocaine solution. Such precipitation was not
re-dispersed by heating or adjusting the pH. Surprisingly, lidocaine is
found to be soluble in 15% or 30% of ketorolac tromethamine solution with
a pH of 7.2. Without being limited to any theory, it appears that the
ketorolac synergistically assists in the solubilization of lidocaine
tromethamine and that such synergy continues even when the amount of
ketorolac is increased. This makes lidocaine uniquely suitable for
reducing the stinging sensation associated with intranasal administration
of ketorolac.

[0078] In some embodiments, the invention provides a composition which is
an aqueous solution suitable for nasal administration to a subject, which
solution comprises [0079] (a) greater than 22.5% w/v to about 38% w/v
of ketorolac, [0080] (b) water, and [0081] (c) a pharmaceutically
acceptable pH adjuster to maintain the solution at a pH of about 4.5 to
8.

[0082] In some embodiments, the invention provides a composition which is
an aqueous solution suitable for nasal administration to a subject, which
solution comprises: [0083] (a) greater than 22.5% w/v to about 38% w/v
of ketorolac or a pharmaceutically acceptable salt thereof, [0084] (b)
about 4% w/v to about 10% w/v of lidocaine or a pharmaceutically
acceptable salt thereof, [0085] (c) water, and [0086] (d) a
pharmaceutically acceptable pH adjuster to maintain the solution at a pH
of about 4.5 to 8.

[0087] In some embodiments, ketorolac is as a racemic mixture.

[0088] In some embodiments, the composition comprises about 25 to 35% w/v
of ketorolac or a pharmaceutically acceptable salt thereof. In some
embodiments, the composition comprises about 28 to 32 w/v of ketorolac or
a pharmaceutically acceptable salt thereof. In some embodiments, the
composition comprises about 30% w/v of ketorolac or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition comprises
ketorolac tromethamine. In some embodiments, the composition comprises
about 30% w/v of ketorolac tromethamine.

[0089] In some embodiments, the composition comprises lidocaine
hydrochloride. In some embodiments, the composition comprises about 4%
w/v to about 7.5% w/v of lidocaine hydrochloride. In some embodiments,
the composition comprises about 5-6% w/v lidocaine hydrochloride. In some
embodiments, the composition comprises about 6% w/v lidocaine
hydrochloride.

[0090] In some embodiments, the composition further comprises a chelator.
In some embodiments, the chelator is disodium edetate.

[0091] In some embodiments, the pH of the composition is about 4.5 to 8.
In some embodiments, the pH is about 4.8 to 7.5. In some embodiments, the
pH is about 7.2.

[0092] In some embodiments, the pH is adjusted by a pharmaceutically
acceptable base. In some embodiments, the pharmaceutically acceptable
base is sodium hydroxide.

[0093] In some embodiments, the composition further comprises a pH buffer
to create optimum pH conditions for both product stability and tolerance
(pH range about 4 to about 8; preferably about 6.0 to 7.5). Suitable
buffers include without limitation tris (tromethamine) buffer, phosphate
buffer, etc. Preferably potassium phosphate NF, potassium phosphate
monobasic, or potassium phosphate bibasic, or a combination thereof is
used to maintain the pH to 7.2. In some embodiments, the composition
comprises up to about 2% w/v of potassium phosphate monobasic. In some
embodiments, the composition comprises about 0.68% w/v of potassium
phosphate monobasic.

[0094] In some embodiments, the composition is contained in a vessel
suitable for spraying the solution into a subject's nostril. In some
embodiments, the vessel having a size suitable to contain about 0.1 to 4
mL of the solution. In some embodiments, the vessel having a size
suitable to contain about 0.2 to 2.4 mL of the solution.

[0095] In some embodiments, the composition is in combination with a label
instruction providing for administration of 50 to about 100 microliters
of the solution per nostril. In some embodiments, the label instruction
provides for administration of about 100 microliters of the solution per
nostril. In some embodiments, the label instruction provides for
administration of about 50 microliters of the solution per nostril.

[0096] In some embodiments, the composition comprises: [0097] (a) about
30% w/v of racemic ketorolac tromethamine, [0098] (b) about 0.01% w/v to
about 0.1% w/v of disodium edetate, [0099] (c) up to about 2% w/v of
potassium phosphate monobasic, [0100] (d) sodium hydroxide to adjust the
pH to 7.2, and [0101] (e) water to 100% w/v.

[0102] In some embodiments, the composition comprises: [0103] (a) about
30% w/v of racemic ketorolac tromethamine, [0104] (b) about 5% w/v to
about 6% w/v lidocaine hydrochloride, [0105] (c) about 0.01% w/v to about
0.1% w/v of disodium edetate, [0106] (d) up to about 2% w/v of potassium
phosphate monobasic, [0107] (e) sodium hydroxide to adjust the pH to 7.2,
and [0108] (f) water to 100% w/v.

[0109] In some embodiments, the composition comprises about 5% w/v of
lidocaine hydrochloride. In some embodiments, the composition comprises
about 6% w/v of lidocaine hydrochloride.

[0110] Another aspect of the invention is the composition of the invention
in a vessel equipped with a device for spraying the composition into a
patient's nasal passage. In some embodiments, the vessel is further
equipped with a metering chamber to measure a desired amount of the
composition to be sprayed to the patient's nasal passage. In some
embodiments, the metering chamber is coupled with the spraying device so
that a patient can simultaneously measure and spray a desired amount
(e.g. a unit dose) of the composition. In some embodiments, the metering
chamber is able to measure from about 50 to about 125 microliters of
liquid. In some embodiments, the metering chamber is able to measure from
about 50 to about 100 microliters of liquid. In some embodiments, the
metering chamber is adjustable. In some embodiments, the metering chamber
is able to measure about 50 microliters of liquid. In some embodiments,
the metering chamber is able to measure about 100 microliters of liquid.

[0111] The unit dose of the compositions of this invention is usually
administered one, two, three, or four times a day, providing an amount
generally efficacious in treating moderate to severe pain, whether of a
pathological or neuropathic origin, such as trauma-inflicted pain,
post-operative pain, migraine, and the like. In general, a subject that
is 18 to 65 years old could receive up to the maximum allowed daily dose.
For example, the dose may be an intranasal administration of ketorolac
per day of 100 microliters or less per nostril of a 30% w/v ketorolac
solution. In some embodiments, the composition can be given up to 4 times
per day.

[0112] It is contemplated that in cases of acute migraine attacks, the
high unit dosages enabled by the compositions of this invention would
allow a relief of the pain and/or inhibit the progression of the pain and
other symptoms of migraine so that, preferably, the patient would not
experience significant migraine pains or related symptoms after the
composition is administered once or twice, and avoid the need of repeated
administration of ketorolac during one migraine episode.

[0113] A subject that is an adolescent or is older than 65 could receive
less ketorolac, for example, by intranasal administration of 50
microliters per nostril of a 30% w/v or by intranasal administration of
100 microliters of a 30% w/v ketorolac formulation to only one nostril or
50 microliters of a 30% w/v ketorolac formulation to each nostril.
Children 12 and under would receive appropriately less. It is
contemplated that the nasal absorption capacity of a child is smaller
than that of an adult, thus a lesser volume, e.g., 50 microliters, to one
or each nostril should be administered to children to avoid discharge.

[0114] It is understood that the exact amount is dependent upon the
attending physician's advice, and will be based the age or weight of the
patient, severity of the pain and other factors known in the art.

[0115] The pharmaceutical compositions and unit dose formulations of this
invention may optionally comprise one or more pharmaceutically acceptable
excipients, including a pharmaceutically acceptable carrier (or diluent).
Of course, the selection of the particular excipients depends on the
desired formulation dosage form, i.e., on whether a solution to be used
in drops or as a spray is desired or whether a suspension, ointment or
gel to be applied directly to the nasal cavity is desired. In any case,
the invention enables the preparation of single-dose or multi-dose dosage
forms, which ensure application of an optimum quantity of drug.

[0116] The preferred carrier for the formulations according to the
invention is water, preferably sterile water, and other excipients may be
added if desired.

[0117] In addition to aqueous, oil or gel diluents, other diluents which
may be used in the compositions according to the invention comprise
solvent systems containing ethyl alcohol, isopropyl alcohol, propylene
glycol, polyethylene glycol, mixtures thereof or mixtures of one or more
of the foregoing with water.

[0119] If present, excipients such as oil, gel, chemical enhancers,
including absorption promoters, etc. should be in an amount that does not
adversely affect the homogeneity and sprayability of the solution.

[0120] The compositions of the invention can also contain a compatible
preservative that ensures the microbiological stability of the active
ingredient. Suitable preservatives include without limitation, methyl
paraoxybenzoate (methyl paraben), propyl paraoxybenzoate (propyl
paraben), sodium benzoate, benzyl alcohol, and chlorobutanol. In some
embodiments, the ketorolac intranasal compositions do not contain a
preservative.

[0121] The bacterial load in the compositions of this invention preferably
does not exceed 100 colony forming units (CFUs) and more preferably does
not exceed about 50 CFUs.

[0122] Illustrative formulations may contain the following ingredients and
amounts (w/v) in addition to ketorolac, lidocaine and water.

[0123] It will be appreciated by those of ordinary skill that ingredients
such as sodium CMC and polymers designated as CARBOPOL exist in many
types differing in viscosity. Their amounts are to be adjusted
accordingly. Different adjustments to each formulation may also be
necessary including omission of some optional ingredients and addition of
others. It is thus not possible to give an all-encompassing amount range
for each ingredient, but the optimization of each preparation according
to the invention is within the skill of the art. The presence of the
excipients should be in an amount that does not adversely affect the
homogeneity and sprayability of the solution.

Methods

[0124] Compositions of the invention are administered to a patient in need
thereof by contacting the patient's nasal passage, with a unit dose or an
amount of the composition sufficient to result in absorption of ketorolac
by the patient to reduce the pain and/or inflammation experienced by the
patient. This is preferably carried out by spraying a solution, as
described herein, into the nasal passage(s) of the patient from a vessel
that is equipped with a device (e.g., an atomizer) for producing a spray
(e.g. atomized particles). The device produces a mist or suspension of
fine liquid particles that are inhaled by the patient into her or his
nasal passage(s) from which it is rapidly absorbed into the bloodstream
to effect its analgesic and anti-inflammatory action. The volume
administered should not exceed the maximum absorption capacity of the
nostril to avoid drug loss through drainage. Appropriate vessels and
spray devices are available to one of skill in the art by referring to
"Remington's Pharmaceutical Sciences." One source for such vessels is
Ing. Erich Pfeiffer GmbH, Radolfzell, Germany. Another source is Valois,
50 avenue de l'Europe, 78164 MARLY-LE-ROI, France.

[0125] In another aspect, this invention provides methods for treating
pain or inflammation in a subject in need of such treatment, comprising
intranasally administering a pharmaceutical composition or a unit dose
formulation of this invention as described above to one or each nostril
of a patient.

[0126] In some embodiments, the unit dose formulation is administered
once, twice, three times or four times a day.

[0127] In some embodiments, the method is for treating pain.

[0128] In some embodiments, the pain is the result of a trauma inflicted
on the subject. In some embodiments, the pain is the result of a medical
operation performed on the subject.

[0129] In some embodiments, the pain is pathological. In some embodiments,
the pain is neuropathic. In some embodiments, the pain is migraine or
other headache pain.

[0130] The following example of a formulation for the intranasal
administration of ketorolac serves to illustrate the invention without
limiting its scope.

Example 1

[0131] This example provides a description for making compositions for
nasal administration in accordance with the invention. A solution was
prepared in accordance with the proportions shown in Table 1.